Prostate is a gland about the size of a walnut that is only present in men. It is located just below a urinary bladder and surrounds the urethra, the tube through which urine flows from the urinary bladder and out through the penis. The urethra passes diagonally through the front of prostate. The ejaculatory ducts on both sides of the prostate penetrate parenchyma behind the urethra. The parenchyma of the prostate is divided into three glandular lobes: middle lobe located above the ejaculatory ducts and side lobes in right and left of the urethra below the ducts. It is of tubulo-alveolar structure and is classified roughly into glandular tissue and interstitial tissue. The interstitial tissue consists of 30 to 50 small glandular lobes, from which prostatic ducts open chiefly into the prostatic sinuses that lie on either side of the seminal colliculus on the posterior wall of the prostatic urethra.
The prostate is one of the male accessory reproductive organs having a reproductive function along with testicles and seminal vesicles. It produces prostatic secretions of about one-third of seminal fluid. The prostatic secretions increase the mobility of sperms by nourishing the sperms produced in the testicles and also by preventing ejaculated semen from congealing, thus aiding the sperms mobility. Moreover, the prostatic secretions of alkaline act as an important vehicle for semen activity, i.e., they neutralize the strong acidic environment of female oviduct to help the sperms to be fertilized with an egg safely.
Benign prostatic hyperplasia (BPH) is a common disorder that affects older men aged above 50 years and is often associated with lower urinary tract symptoms (LUTS), thus deteriorating an individual's quality of life. The primary predisposing factors that spur the development of BPH are the aging and the presence of male hormones (androgens). Judging from the fact that men who have innate testicular insufficiency or whose testicles were removed are not affected with BPH, it can be understood that the male hormones participate in BPH as a predisposing factor. Besides, the differences of human species, environments, dietary lives, etc. may become the predisposing factors of BPH.
In general, the presence of histological BPH is in men aged 30 to 40 years, the incidence increases to the most men in aged above 60 years, and above 50% of enlarged prostates develop into those palpable with increasing ages [Prostate 1996 (suppl. 6) 67-73]. In is general, above 30% of tissue in the prostate have fibromuscular characteristics and it relates anatomically and functionally to the urinary bladder (Prostate 1981 2:35-49).
The symptoms of BPH include a hesitant, interrupted and weak stream; urgency and leaking or dribbling; and more frequent urination, especially at night. Since these symptoms develop slowly over the long haul, such symptoms may be considered simply as those caused by the aging process, which may develop in serious conditions such as hydronephrosis or uremia.
The diagnosis of BPH is carried out initially by identifying the degree of the symptoms and by palpation of the prostate through the rectum. For an accurate diagnosis, thorough examinations such as urodynamic studies, ultrasonography, etc., are referred to and treatment options are decided based on the results of such examinations.
Lower urinary tract symptoms (LUTS) may be caused by obstruction of the urinary tract due to an enlarged prostate consisting of epithelial cells and smooth muscles, reaction of the urinary bladder against the obstruction of the urinary tract, and strong contractions of smooth muscles due to stimuli of alpha-sympathetic nerves. Various symptoms related to processes of storing and voiding urine are collectively called lower urinary tract symptoms (LUTS). Storing difficulty symptoms include frequent urination, urgent urination, urgent incontinence, night urination (nycturia), painful urination (dysuria), etc. Voiding difficulty symptoms include hesitant urination, stress urination, weakened ureter, residual urine sense, urinary retention (anuresis), etc.
A variety of structural or medical conditions can cause LUTS, and it has been known that the predisposing factors of LUTS are bladder outlet obstruction, abnormalities in detrusor contraction, detrusor overactivity, etc., however, the primary factor is urethral obstruction by BPH. Accordingly, it has been considered that the treatment of the urethral obstruction lessens LUTS.
The treatments for BPH, the primary factor of LUTS, are classified roughly into surgery and drug therapies. The most available treatment for BPH was surgery even ten years before; whereas, drug therapies using alpha-receptor blockers, drugs for relaxing the smooth muscle that surround the prostate, and 5-alpha-reductase inhibitors, drugs for reducing the volume of the prostate, have been introduced recently. Moreover, with the development in the biomedical engineering field, newer methods capable of treating BPH, not dependent upon surgery, such as balloon dilatation, hyperthermia, laser therapy, transurethral needle ablation (TUNA), etc., have been developed and wide used.
Since it has been known that the alpha-receptors play an important role in the tension of smooth muscles in various tissues, their blockers have been applied to treatment of hypertension ahead of time. The typical alpha-receptor blocker is quinazolines such as alfuzocin, terazosin, doxazosin, prazosin, tamsulosin, etc. The alpha-blockers for relaxing the smooth muscle adjacent to the prostate are used for treatment of urethral obstruction and dysuria due to BPH. Such drugs can be used in the treatment of hypertension. Since such drugs may cause acute hypotension, sleepiness, dizziness, etc. for 30 to 120 minutes after administration, patients should administrate the drugs at night if possible and be careful when sitting down or sitting up in beds.
Since uroselective alpha-blockers like tamsulosin recently developed operate on contraction of the prostatic smooth muscle more selectively than existing alpha-blockers, they have advantages in that they cause few side effects comparatively and improve patient compliance. However, since the alpha-blockers direct expand the urethra to solve the dysuria, they also have drawbacks in that the treatment using such drugs returns to its initial state if stopping the drug administration. On the other hand, the 5-alpha-reductase inhibitors such as finasteride gradually reduce the volume of the prostate. That is, the 5-alpha-reductase inhibitors block dihydrotestosterone (DHT) that enlarges the prostate to reduce the volume of the enlarged prostate, thus increasing uroflow and relieving the dysuria in the long term. Besides, the 5-alpha-reductase inhibitors have advantages in that they can be administrated along with other drugs for hypertension, circulators, antibiotics, etc., since they have no interactions with other drugs. At the same time, the 5-alpha-reductase inhibitors have drawbacks in that patients should administrate the drugs over minimum six months steadily in order to improve related conditions, and they may cause side effects such as hyposexuality, impotence, decrease of ejaculate, etc.
One of the major factors of LUTS is that the alpha-receptors increase the tension of the smooth muscles in prostatic capsule and bladder neck by contraction and relaxation of the prostatic smooth muscle. Accordingly, the alpha-receptor blockers relax the tension of the prostatic smooth muscle to improve LUTS. However, such alpha-receptor blockers have no selectivity capable of distinguishing three types of al-receptors and have the same affinities as those al-receptors. As a result, they may be associated with side effects due to vasodilation, such as dizziness, asthenia, etc. (European Urology 2005 47:824-837).
Testosterone, one of the predisposing factors of BPH, is converted into 5-a-dihydrotestosterone via 5-a-reductase in the prostate. The 5-a-dihydrotestosterone affects the development and growth of the prostate. Accordingly, the 5-a-reductase inhibitors reduce the volume of the enlarged prostate by inhibiting testosterone from being converted into 5-a-dihydrotestosterone, thus providing desirable efficacies for LUTS (BJU International 2005 96:237-243, Clinical Therapeutics 2006 28:13-25). However, it has been known that the 5-a-reductase inhibitors reducing the volume of the prostate induce sexual dysfunctions (European Urology 2005 47:824-837).
Meanwhile, it has been reported recently that phosphodiesterase-5 (PDE-5) inhibitors, well known as effective ingredient for the treatment of male impotence, act on BPH and various conditions related to BPH (Urol clin North Am 2005 32:511-525; BJU Int 2002 90:836-839) which will now be described in detail hereinafter.
Functions of storing and expelling urine in the lower urinary tract depend on the nervous mechanism controlling various components of urethral outlet and activities of bladder. In general, the nervous system controls detrusor, urethral stump and external urethral sphincter to control uroflow (Journal of Urology 1995 153:2004-2009). Nitric oxide (NO) is a neurotransmitter, released from non-adrenergic, non-cholinergic nerves, which acts on urethral smooth muscle to facilitate the relaxation of urethra (Journal of Pharmacology 1998 357:213-219).
Moreover, one of the conditions related to LUTS is endothelial dysfunction, which is called a state that endothelial-dependent vasodilatation is weakened due to the decrease in activity of nitric oxides. Nitric oxides produced by endothelial nitric oxide synthase (eNOS) activate guanylate cyclase. Activated guanylate cyclase induces the vasodilation, as a result of increasing c-GMP. Meanwhile, the decrease in activity of nitric oxides results from the degenerated antioxidation defense mechanism, manifestation or decreased activity of eNOS, and destruction by active oxygen. The nitric oxides, which are present in the prostate, control the prostatic smooth muscle and prevent the contraction of bladder that induces it hyperactivity, thus reducing LUTS (European Urology 2005 47:824-837). Accordingly, nitric oxide donors that relax the urethral smooth muscle and the prostatic smooth muscle can improve LUTS.
Sildenafil, one of the conventional PDE-5 inhibitors, inhibits the activity of PDE-5 that decomposes c-GMP to relax the prostatic smooth muscle via c-GMP route associated with nitric oxides (BJU International 2002 90:836-839).
The inventors of the present invention have disclosed WO2000/027848 (Corresponding Korean Patent No. 0353014), in which a novel pyrazolopyrimidinone compound is prepared to have efficacy on inhibition of PDE-5. Then, the inventors of the present invention have continued to study on the pyrazolopyrimidinone compound, one of the PDE-5 inhibitors, and confirmed that the pyrazolopyrimidinone compound shows more excellent efficacy on benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) associated with BPH than the conventional sildenafil. Moreover, the inventors of the present invention have verified that since the pyrazolopyrimidinone compound has an in vivo half-life longer than the other PDR-5 inhibitors, the administration convenience is increased and the time required for reaching a maximum blood concentration is shortened; and since the pyrazolopyrimidinone compound is less affected by the liver metabolism as compared with the other drugs, the possibility of side effects by interactions between drugs is very low (Xenbbiotica 2004 34:973-982) and completed the present invention.